This proposal focuses on the elucidation of the role of co-stimulation in the defense against virally induced neoplasma. Virally-induced neoplasms are a major cause of morbidity and mortality in humans that are chronically immunosupressed, as in transplant recipients, patients treated for autoimmune disorders, and the acquired immune deficiency syndrome (AIDS). Virally induced tumors include Kaposi's sarcoma, caused by HHV8, non-Hodgkins lymphoma, caused by Epstein-Barr virus, and cutaneous and cervical carcinoma caused by human papilloma virus. In order for these acquired viruses to cause cancer in humans, the immune system must tolerate viral antigens. We have developed a murine model of a virally-induced endothelial tumor, analogous to Kaposi's sarcoma. This tumor, SVR, was derived by the sequential introduction of SVRO large T antigen and oncogenic H-ras into murine microvascular endothelial cells, and is highly tumorigenic in nude mice, but is rejected by syngeneic C57BL6 mice. We wish to determine the role the costimulatory dependent and independent pathways involved in the rejection of a virally induced endothelial tumor. This knowledge may allow therapeutic immune suppression without the potentially lethal consequences of virally-induced neoplasia. In addition, this model could be useful for evaluating novel immunosuppressive therapies, since the endothelium is the first target for immune rejection in solid organs. Specific Aims: 1) We will determine the role of CD4 and CD8 T lymphocyte subsets in the rejection of SVR tumors in syngeneic mice. 2) We will determine the role of the co-stimulatory molecules CD28, CD40, and CD40 ligand (CD40L) in the rejection of SVR tumors. 3) We will determine whether the presence of lymphoid tissue and spleen is required for rejection of SVR cells.